This invention generally relates to the field of therapeutic agents useful in the treatment of Parkinson's disease and other diseases associated with reduced neuronal metabolism of glucose, including for example, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), Huntington's disease, and epilepsy.
Diseases such as Parkinson's disease are marked by a reduced ability of neuronal cells to metabolize glucose as an energy source. It has been demonstrated that ketone bodies (acetoacetate and 3-hydroxybutyrate) serve as alternate energy sources for the brain when glucose supplies are limited. Ketone bodies formed by the body through use of a ketogenic diet have been shown to alleviate symptoms of Parkinson's disease in humans. However, ketone bodies cannot be provided directly to the human body in an acid form because a metabolic acid imbalance can result. Likewise, if such ketone bodies are provided in their salt form (e.g., Na or K salt forms), a salt electrolytic imbalance can result due to the excess quantities of such ketone bodies used to produce the desired effect. Further, the ketogenic diet is difficult to maintain for a prolonged period of time, as the diet is severely restricted to low-carbohydrate, low-protein, high fat foods.
In general, ketone bodies are normal components of blood plasma. They can be produced in the liver from the metabolism (oxidation) of fatty acids when low amounts of carbohydrates are available. Acetoacetate is one of the two main ketone bodies produced by the human body, the other is 3-hydroxybutyrate (3HB). Acetoacetate can also be reduced in the mitochondria of cells to form 3HB. Once these types of ketone bodies are produced, they can be transported to peripheral tissues (heart, skeletal muscle, kidney, etc.) for use as an energy source. In particular, the brain utilizes ketone bodies when sufficient glucose is not available for energy.
Moreover, ketone bodies are typically produced in small quantities, and because they are rapidly utilized, their concentration in the blood is normally very low. In a healthy human subject, the level of ketone bodies is normally 0.1 mM or less after the consumption of a food source. Blood ketone body concentrations rise where a low carbohydrate diet is utilized, during periods of fasting, or under conditions where glucose may be lowered such as diabetes, for example. Upon overnight fasting, the levels of ketone bodies in a healthy human subject can typically rise to about 0.3 mM. After a three day fast, the level can rise to about 3.0 mM; the levels can climb to about 7 mM after a 24 day fast. (Fenselau, 1981). It has been determined that the maximum capacity for generating ketone bodies (ketogenesis) of the human liver is about 130 g/day. Owen O E, Reichard G A J, Human forearm metabolism during progressive starvation, J. Clin. Invest., 50:1538-1545 (1971). In cases of prolonged starvation, acetoacetate can provide more than 70% of the brain's energy requirements without cellular damage.
Additionally, a ketogenic diet has been successfully used since the 1920's to treat both children and adults with medication-resistant seizure disorders. The diet is based on the brain's ability to utilize ketones as an energy source by mimicking the metabolic effects of fasting while food is being consumed. By eating a high-fat, low-carbohydrate, and low-protein diet, blood ketone levels can be increased and maintained at therapeutic concentrations of 2-8 mmol/L. Such levels are well below the dangerous levels observed in uncontrolled diabetes. Further, such an outcome illustrates that the ketogenic diet treatment can increase blood ketone concentrations to a therapeutically significant level, while avoiding toxicity.
The ketogenic diet, however, is difficult to maintain for a prolonged time. The diet is severely restrictive, and the high fat levels it contains may lead to an undesirable increase in serum low-density lipoprotein (LDL) cholesterol levels and other potentially atherogenic serum lipids. VanItallie et al., Treatment of Parkinson disease with diet-induced hyperketonemia: A feasibility study, Neurology, 64:728-730 (2005).
As an alternative, medium chain triglycerides have been used as part of a ketogenic diet since they are readily metabolized to form ketone bodies. U.S. Pat. No. 6,835,750 (Henderson) proposes the use of medium chain triglycerides to produce ketone bodies upon oxidation to treat conditions marked by impaired glucose metabolism in the brain, such as Alzheimer's disease.
Zhao et al (2006) appeared to describe that a ketogenic diet has the potential to alleviate symptoms of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) in test animals. Zhao et al., A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis, BMC Neuroscience, 7:29 (2006).
A human clinical trial by VanItallie et al (2005) appeared to observe and describe the potential for a ketogenic diet to alleviate the symptoms of Parkinson's disease. Neurology, 64:728-730. However, because the diet is so restrictive and therefore difficult to maintain, the number of test subjects was limited.
It would therefore be desirable to directly provide ketone bodies as an energy source to humans or animals, especially those suffering from conditions involving reduced neuronal glucose metabolism. It is difficult to administer the free acid forms of ketone bodies in humans, as this can induce metabolic acidosis. Use of the sodium salts is also not desirable, as sodium ion overload will occur at the amount of ketone bodies needed to achieve desired plasma concentrations.
The glycerol esters of acetoacetate and 3-hydroxybutyrate have been used to provide ketone bodies for their protein-sparing function. It has been reported in the following references that sufficient levels of ketone bodies in the body could be achieved without detrimental side effects.
For example, studies by Birkhahn and Border demonstrated that monoacetoacetin (the ester corresponding to 1 mole of glycerin and 1 mole of acetoacetate) could be safely infused into rats at the rate of up to at least 50 g/kg body weight/day, a level providing the equivalent of 2/3 the rat's daily caloric requirement. Amer. J. Clinical Nutrition 31:436-441, Intravenous Feeding Of The Rat With Short Chain Fatty Acid Esters. II. Monoacetoacetin (1978); J. Nutr. 109:1168-1174, Monoglyceryl Acetoacetate: A Ketone Body-carbohydrate Substrate For Parenteral Feeding Of The Rat (1979). According to Birkhahn and Border, elevated levels of ketone bodies were thus achieved without any detrimental side effects in the test subjects. The authors concluded from the observations that monoacetoacetin was providing energy to the rat. In this study, the ketone bodies were being utilized for their ability to spare protein. No mention was made of the potential for monoacetoacetin to provide ketone bodies to provide energy for the brain and to address conditions associated with reduced neuronal glucose metabolism.
In WO 95/09146 (Eastman Chemical; Medical College of Ohio), the use of bisacetoacetin (the ester corresponding to 1 mole of glycerin and 2 moles of acetoacetate) for parenteral nutrition was described. Bisacetoacetin was infused into patients at a level corresponding to 8-9.3 g/Kg body weight/day to affect hyperketonemia. No detrimental side effects were said to be observed. In this study, the ketone bodies were being utilized for their ability to spare protein. No mention was made of the potential for diacetoacetin to provide ketone bodies as an alternative energy source for the brain to address conditions associated with reduced neuronal glucose metabolism.
U.S. Pat. No. 5,093,044 (Kabivitrum AB) generally describes the use of triacetoacetin as a nutrient for animals and humans. In the reported studies, rats allegedly tolerated triacetoacetin at the amount of 10 g/Kg body weight/day. In these studies, the ketone bodies were being utilized for their ability to spare protein. No mention was made of the potential for triacetoacetin to provide ketone bodies as an alternative energy source for the brain to address conditions associated with reduced neuronal glucose metabolism.
U.S. Pat. No. 6,380,244 (Metabolix, Inc.) describes the use of oligomers of 3-hydroxyalkanoic acids for providing ketone bodies to the body. The reference does not disclose the use of glyceride esters.
WO 95/09144 (Eastman Chemical; Medical College of Ohio) generally describes the use of 1-(DL-3-hydroxybutyryl)-glycerol in parenteral nutrition to replace glucose. It does not discuss the treatment of conditions associated with reduced neuronal glucose metabolism through the use of glyceride esters. In the described rat feeding studies, it was observed that both 1-(DL-3-hydroxybutyryl)-glycerol and DL-tris-(3-hydroxybutyrl)-glycerol were not acutely toxic and did not show any indication of chronic toxicity.
Tieu et al (2003) have observed that direct administration of 3-hydroxybutyrate can protect mice against a neurotoxin known to induce Parkinson's disease. Tieu et al., D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease, J. Clin. Invest. 112:892-901 (2003). No mention in the reference, however, was made of the potential to use glyceride esters of 3-hydroxybutyrate or as an alternative energy source for neuronal glucose metabolism disorders.
The present technology provides a readily utilized alternative source of energy for the brain and other tissues of a human or animal in the form of glyceride esters of ketone bodies. The present technology also provides one or more compositions useful in the treatment or prevention of neuronal glucose metabolism diseases and/or disorders.